No means no for PTC's Translarna

PTC Therapeutics's last-ditch effort to gain approval over a US FDA rejection looks like it will be no more successful than the first. An advisory panel voted that more work would be needed to establish whether Translarna, PTC’s nonsense mutation-directed project, is effective at improving mobility in patients with Duchenne muscular dystrophy.

Now with the thumbs down from an advisory committee and a previous refuse-to-file decision by the regulator, the outcome seems obvious: PTC will need to return to the clinic to see if it can show duplicate a fleeting benefit in six-minute walk test more robustly. That the FDA even needed to call in its experts shows that the agency is reaping what it has sown with the decision to approve Sarepta's Exondys 51, as PTC employed many of the same public-relations tactics.

Somewhat unusually the advisory panel was asked to choose between three options: that the data presented suggested that Translarna was ineffective, that they were inconclusive, or that they were sufficient to conclude effectiveness. Normally panellists are asked a simple yes/no as to whether benefits outweighs risks.

Only one panellist voted that the evidence supporting Translarna, known generically as ataluren, shows it to be effective. The remaining 10 said the data were inconclusive and more work was required.

Unusual process

The benefit shown on the six-minute walk test in certain subgroups was not compelling, and neither was the "U-shaped" dose response in which an efficacy signal was strongest only in a medium dose.

As with Exondys 51, a strong signal in an intermediary endpoint like six-minute walk can be enough to gain accelerated approval, but only if it is strong and consistent; FDA officials told the panellists that Translarna did not meet these criteria. As for use of post-hoc subgroup analyses, FDA officials said these were useful in designing future work, but could not necessarily be relied upon as a conclusive sign of efficacy.

There was no pretending that amicable relations existed between PTC and the US regulator. The two had fallen out when the FDA slapped Translarna with a refuse-to-file letter, and the biotech group pressed the nuclear button with a filing “over protest”, resulting in its advisory panel and an October 24 PDUFA date.

It is true that, barring a subgroup benefit, Translarna’s phase III ACT DMD study was a failure, but PTC actually held two moderately strong cards: Translarna had somehow managed to get EU conditional approval, and there was the precedent of Sarepta’s Exondys 51 – approved on paper-thin data thanks to extensive patient lobbying.

Sarepta: The sequel

And there was no doubt that PTC was playing the Sarepta card. The FDA’s briefing documents, released before the adcom, painted a rarely seen picture of the shenanigans that had gone on behind the scenes, including PTC’s direct claim that the FDA was being unfair and inconsistent in its treatment of Translarna compared with Expondys 51 and Biomarin’s drisapersen.

The FDA fought back, stating in the briefing documents that drisapersen had been supported by one “apparently positive” trial, and Exondys 51 by a historically controlled study that Sarepta had “presented ... as positive”.On Translarna, however, the agency did not mince its words, calling PTC’s data “clearly and convincingly negative”.

More seriously, the briefing documents also poured scorn on PTC’s claim to the markets that patients with a six-minute walk distance of 300-400m at baseline, which yielded a positive benefit, amounted to a prespecified subgroup.

“It is true that [this] subset was mentioned in the statistical analysis plan, but there was clearly no planned use of these as primary study endpoints, and they cannot properly be described as planned or pre-planned,” the agency stated.

The briefing documents also provided a rare insight into communication between the agency and a sponsor, reproducing Translarna’s refuse-to-file letter in full. This cited PTC’s two failed studies and multiple post hoc adjustments as the main reasons for rejection.

At least PTC can say it has started to address some of the FDA's objections in the form of a long-term outcomes trial necessary to confirm the EU's conditional approval. As this started recruiting only a few months ago, outcomes will not be known for a couple of years – patients will be dosed for 72 weeks.

PTC will probably persist after its latest FDA knockback. It will also know the standard of evidence it will need to meet next time around – the FDA is eager to make Sarepta the exception, not the rule.